Coregistration of clinical magnetic resonance imaging (MR1) and post-mortem brain, together with non-biased stereologieal cell-counting methods, will be used to determine the pathological substrate of several cortical and subcortical neuroimaging changes associated with small-vessel cerebrovascular disease (CVD) and Alzheimer disease (AD). Specific Aim 1: To improve co-registration of post-mortem brain to clinical MRI by reducing geometric distortions and applying compensatory polynomial warping algorithms. Specific Aim 2: Although hippocampal atrophy is an early hallmark of AD, it may also occur in subjects with s-CVD. Hippocampal volume (HV), glucose metabolism (CMRglc), and N-acetyl aspartate [NAA] will be correlated with numbers and size of neurons in s-CVD and AD. Specific Aim 3: Although s-CVD is currently conceptualized as a subcortical disease, new findings during the initial funding period indicate that cerebral cortical changes (atrophy, decreased CMRglc and [NAA]) also occur. Cortical gray matter volume, CMRglc, and [NAA] will be correlated with number and size of cortical neurons to determine whether a) cortical changes in s-CVD represent neuronal shrinkage secondary to deafferentation, or b) primary neuronal loss due to ischemic injury or other factors. Specific Aim 4: Confluent white matter lesions (WML) are highly prevalent in s-CIVD, where they are believed to represent areas of myelin and axon loss due to ischemia. The volume and fractional anisotropy of WML will be correlated with numbers of oligodendrocytes, seventy of demyelination and axon loss, and seventy of microvascular disease. Specific Aim 5: Subcortical focal hyperintensities in proton density MRI (L) are considered to be lacunar infarcts. Because many of these lesions are clinically "silent," the question is posed: Do all hyperintensities represent lacunar infarcts or possibly other types of pathology (e.g., gliosis or incomplete infarction)? The goal of this project is to advance understanding of pathological changes and to clarify the diagnostic utility of several highly prevalent neuroimaging findings associated with s-CVD.